Use of substituted-3(2,3-dihydro-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-diones for treating grey matter edema

ABSTRACT

The invention relates to novel substituted-3-(2,3-dihydro-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-diones, their analogs and their salts. These compounds are synthesized by methods selected from a number of synthetic routes depending on the particular structure, choice of intermediate or preferred reaction sequence. The compounds are useful for the treatment and prevention of injury to the brain and of edema due to head trauma, stroke (particularly ischemic), arrested breathing, cardiac arrest, Reye&#39;s syndrome, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, cerebral tumors, encephalomyelitis, spinal cord injury, hydrocephalus, post-operative brain injury trauma, edema due to cerebral infections and various brain concussions.

BACKGROUND OF THE INVENTION

Trauma to the brain or spinal cord caused by physical forces acting onthe skull or spinal column, by ischemic stroke, arrested breathing,cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism,cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operativebrain injury, cereral infections and various concussions results inedema and swelling of the affected tissues. This is followed byischemia, hypoxia, necrosis, temporary or permanent brain and/or spinalcord injury and may result in death. The tissue mainly affected areclassified as grey matter, more specifically astroglial cells. Thespecific therapy currently used for the treatment of the medicalproblems described include various kinds of diuretics (particularlyosmotic diuretics), steroids (such as, 6-α-methylprednisolone succinate)and barbiturates. The usefulness of these agents is questionable andthey are associated with a variety of untoward complications and sideeffects. Thus, the compounds of this invention comprise a novel andspecific treatment of medical problems where no specific therapy isavailable.

A recent publication entitled Agents for the Treatment of BrainInjury 1. Aryloxyalkanoic Acids, Cragoe et al, J. Med. Chem., (1982) 25,567-79, reports on recent experimental testing of agents for treatmentof brain injury and reviews the current status of treatment of braininjury.

In addition, some compounds having structures related to the compoundsof the present invention have been reported as being useful in thetreatment and prevention of calcium oxalate kidney stone formation inU.S. Pat. No. 4,342,776 of Cragoe et al. There is, however, nosuggestion in the patent that any of the compounds disclosed thereinwould be of use in the treatment of brain injury.

The compounds of the invention have the added advantage of being devoidof the pharmacodynamic, toxic or various side effects characteristic ofthe diuretics, steroids and barbiturates.

DESCRIPTION OF THE INVENTION

The compounds of the instant invention are best characterized byreference to the following structural formula (I). ##STR1## wherein R iscycloalkyl (C₃ to C₆), cycloalkyllower alkyl (C₄ to C₇ total), aryl,such as phenyl, substituted aryl, such as phenyl with substituents, suchas halo, methyl, methoxy, and hydroxy, heterocyclic such as thienyl,aralkyl, such as benzyl and phenethyl, lower alkyl, branched orunbranched, lower alkenyl, branched or unbranched and lower alkynyl andthe like. R¹ is lower alkyl, branched or unbranched, alkenyl or alkynyland the like. X and Y are chloro or methyl and the like and A is a bond,--O--, or --O(CH₂)_(q), where q is 1 to 5 and Z is O or H and OH.

When the R and R¹ substituents are different, the 2-position carbon atomof the indane ring is asymmetric and these compounds of the inventionare racemic. However, these compounds or their precursors can beresolved so that the pure enantiomers can be prepared, thus theinvention includes the pure enantiomers. This is an important pointsince some of the racemates consist of one enantiomer which is much moreactive than the other one. Furthermore, the less active enantiomergenerally possesses the same intrinsic toxicity as the more activeenantiomer. In addition, it can be demonstrated that the less activeenantiomer depresses the inhibitory action of the active enantiomer atthe tissue level. Thus, for three reasons it is advantageous to use thepure, more active enantiomer rather than the racemate.

An example of this is seen with the compound of Example 1, which is(+)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione1-methylpiperazine salt which is much more active than the(-)-enantiomer described in Example 23. Thus, by using the pure(+)-enantiomer, not only has the much less active component of theracemate been eliminated but its unwanted contribution to toxicity andside effects abolished and its detrimental effect on intrinsic activityhas been eliminated.

With the compounds where Z is H and OH, i.e. those where there is ahydroxy group on the 1-position of the indane ring, a second asymmetriccarbon atom (the 1-position of the indane ring) is established.Therefore, the compounds where Z is H and OH and R and R¹ are differentconsist of two diastereomers, each of which is a racemate. However, thediastereomers can be separated by fractional crystallization orchromatography. When intermediates which are preresolved at the2-position of the indane ring, reduction of a 1-indanone to a 1-indanolproduces two diastereomers, each consisting of a single enantiomer,which can be separated by fractional crystallization or chromatography.This type of compound is illustrated by Examples 32 and 33.

Since the products of the invention are acidic, the invention alsoincludes the obvious pharmaceutically acceptable salts, such as thesodium, potassium, ammonium, trimethylammonium, piperazinium,1-methylpiperazinium, guanidinium, bis-(2-hydroxethyl)ammonium,N-methylglucosamonium and the like salts.

It is also to be noted that the compounds of Formula I, as well as theirsalts of Formula I-G, often form solvates with the solvents in whichthey are prepared or from which they are recrystallized. These solventsmay be used per se or they may be desolvated by heating (e.g. at 70° C.)in vacuo.

Although the invention primarily involves novelsubstituted-3-(2,3-dihydro-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-diones,and their salts, it also includes their derivatives, such as oximes,hydrazones and the like.

In accordance with one aspect of the present invention, there isincluded a novel group of compounds which are pure enantiomers ofcompounds of Formula I-A: ##STR2## wherein X, Y, R and R' are defined ashereinabove, provided that R and R' are not the same entities, and thepharmaceutically acceptable salts thereof, as well as pharmaceuticalcompositions in unit dosage form containing an effective amount of oneof the compounds encompassed by the above formula and the method oftreating brain injury using one of said pharmaceutical compositions.

Also included in this aspect of the invention are novel racemiccompounds in which R is cycloalkyl, cycloalkyl-lower alkyl, arylselected from phenyl, halophenyl, methoxyphenyl, hydroxyphenyl,heterocyclic, including thienyl, aralkyl selected from benzyl andphenethyl, lower alkyl, lower alkenyl, lower alkynyl; and R' is loweralkyl, lower alkenyl or lower alkynyl, provided that R is not cycloalkylor alkyl when R' is lower alkyl and both X and Y are chloro, and themethod of treating brain injury using said novel racemic compounds.

In accordance with a second aspect of the present invention, there isincluded a novel group of diastereomers and their enantiomers ofcompounds of Formula I-B: ##STR3## wherein X, Y, R and R' are as definedhereinabove, provided that R and R' are not the same entities, saiddiastereomers being derived by reduction of a pure enantiomer,particularly the pure (+)-enantiomer of the corresponding 1-oxocompound, as well as pharmaceutical compositions in unit dosage formcontaining an effective amount of one of the compounds encompassed by adiastereomer of the above formula. Also included are the correspondingracemic compounds wherein, X, Y, R and R' are defined as hereinaboveprovided that R is not cycloalkyl or alkyl when R' is lower alkyl and Xand Y are both chloro.

In accordance with a third aspect of the present invention, there isincluded a novel group of compounds of Formula I-C: ##STR4## wherein X,Y, R and R' are as defined hereinabove including, when R and R' aredifferent entities, the racemic compounds and the (+)-enantiomers ofsaid racemic compounds and pharmaceutical compositions in unit dosageform containing an effective amount of one of the defined compounds or a(+)-enantiomer thereof.

In accordance with a fourth aspect of the present invention, there isincluded a novel group of diastereomers and their enantiomers of FormulaI-D: ##STR5## said diastereomers being derived by reduction of the pureenantiomer, especially the pure (+)-enantiomer of the corresponding1-oxo compound, as well as pharmaceutical compositions in unit dosageform containing an effective amount of one of the novel deriveddiastereomers. Also included are the corresponding racemic compoundswherein X, Y, R and R' are defined as hereinabove provided that R is notcycloalkyl or alkyl when R' is lower alkyl or cycloalkyl and X and Y areboth chloro.

In accordance with a fifth aspect of the present invention, there isprovided a novel group of compounds of Formula I-E: ##STR6## wherein Z,X, Y, R, R' and q are as defined hereinabove and the optical isomersthereof, wherein R and R' are different entities, and/or Z is H and OH,as well as pharmaceutical compositions in unit dosage form containing aneffective amount of a compound of the above formula or a pureenantiomer, particularly the (+)-enantiomer or diastereoisomer derivedtherefrom by reduction of the corresponding 1-oxo compound.

PREFERRED EMBODIMENT OF THE INVENTION

The preferred embodiments of the instant invention are realized instructural Formula I-F wherein: ##STR7## R² is cyclopentyl, phenyl orbenzyl Z is as defined before.

R³ is lower alkyl, alkenyl and alkynyl, and A¹ is a bond, --O--, andO(CH₂)_(q-) where q is 1 to 4.

Also included are the diastereomers and the enantiomers of eachracemate.

Preferred compounds are(+)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its nontoxic salts.

Other preferred compounds are 3-(2-butyl-B6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione,and its (+)-enantiomer and their pharmaceutically acceptable salts.

Other preferred compounds are3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]4-hydroxy-1H-pyrrole-2,5-dione.

Other preferred compounds are3-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione,its (-) enantiomer and their pharmaceutically acceptable salts.

Other preferred compounds include3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione,its (+)-α-diastereomer and the (+)-β-diastereomer (each of which arepure enantiomers) and their pharmaceutically acceptable salts.

Other preferred compounds include3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione,its (+)-α-diastereomer, its (+)-β-diasterisomer (each of which are pureenantiomers) and their pharmaceutically acceptable salts.

Other preferred compounds include the (+)-α-diastereomer and(+)-β-diastereomer and3-[2-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dione,each of which consists of a single pure enantiomer.

Especially preferred are the pure enantiomers since, in most instances,one enantiomer is more active biologically then its antipode.

Included within the scope of this invention are the pharmaceuticallyacceptable salts of the parent3-substituted-4-hydroxy-1H-pyrrole-2,5-diones since a major medical useof these compounds is solutions of their soluble salts which can beadministered parenterally.

Thus, the acid addition salts can be prepared by the reaction of the3-substituted-4-hydroxy-1H-pyrrole-2,5-diones of this invention with anappropriate amine, ammonium hydroxide, guanidine, alkali metalhydroxide, alkali metal carbonate, alkali metal bicarbonate, quaternaryammonium hydroxide and the like. The salts selected are derived fromamong the non-toxic, pharmaceutically acceptable bases.

The synthesis of the 3-substituted-4-hydroxy-1H-pyrrole-2,5-diones ofFormula I are generally carried out by the reaction of the appropriateamide (Formula II) with diethyl oxalate in the presence of a base and asolvent. ##STR8## Advantageously, the base that is used can be potassiumtert.-butoxide but other bases, such as sodium ethoxide or potassiummethoxide can be used. The use of dimethylformamide is especiallyadvantageous as a solvent but other polar, inert solvents such as1-methyl-2-pyrrolidinone can be used. The reaction is generallyconducted at the ambient temperature but it can be conducted attemperatures as low as 10° C. and as high as 50° C. for periods of timeof 6 to 24 hours, depending on the specific reactants.

The reaction can be conducted using amides of Formula II which aremixtures of diastereomers, pure diastereomers, racemates or pureenantiomers and, thus, obtain the corresponding3-substituted-4-hydroxy-1H-pyrroline-2,5-diones of Formula I as mixturesof diastereomers, pure diastereomers, racemates or pure enantiomers.

Some 3-(2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dionesof the instant invention are advantageously prepared by the oxidation ofthe corresponding3-(2,3-dihydro-1-hydroxy-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-diones.Advantageously this is carried out using an oxidizing agent, such asJones reagent (CrO₃ in dilute sulfuric acid) using a solvent, such asacetone, 2-butanone, and the like. The reaction is generally conductedat ambient temperatures but temperatures in the range of 10° to 40° C.can be used.

The preparation of the intermediate amides of Formula II is carried outby any one of several methods involving the reaction of the appropriateester Formula III, acid chloride of Formula IV or acylimidazole ofFormula V with ammonia. ##STR9## The reaction of an ester of Formula IIIis generally carried out in a solvent such as dimethylformamide or1-methyl-2-pyrrolidinone and then ammonia in a solvent, such as methanolor ethanol, is added. Ambient temperature is advantageously employed buttemperatures as low as 10° C. or as high as 100° C. can be used;however, when higher temperatures are employed, it is necessary to use asealed vessel to contain the ammonia. The reaction time varies,depending on the temperature and may require from twelve hours to fourweeks.

When an acid chloride of Formula IV is used, the reaction is generallyconducted in an inert solvent, such as methylene chloride or benzene andthe ammonia added in a solvent like ether of a mixture of ether andmethylene chloride. Usually it is also advantageous to introduce ammoniagas and finally aqueous ammonia. The reaction is generally conducted attemperatures in the range of 0° C. to 10° C. but, if a sealed reactionvessel is used, temperatures of 10° to 50° C. can be used. The reactiontimes are generally in the range of 10 minutes to two hours.

When an amide of Formula II is prepared from an acylimidazole of FormulaV, a solvent, such as tetrahydrofuran or dioxane is employed since theacylimidazole is generated in that solvent. Then, the acylimidazole istreated with ammonia gas or aqueous ammonia. The reaction is generallycarried out at ambient temperatures but temperatures as low as 10° C. oras high as 50° C. can be used.

The preparation of amides of Formula II-A, i.e. those in which Z=H+OHare best prepared by reduction of the corresponding compound of FormulaII-B where Z=O. The reduction is advantageously conducted using sodiumborohydride in a solvent like ethanol at room temperature for a periodof 1 to 5 hours. ##STR10##

One method for the preparation of the intermediate esters of Formula IIIis carried out by esterification of the appropriate carboxylic acid ofFormula VI. ##STR11##

The reaction is conducted using the appropriate alcohol (Alkyl--OH) suchas methanol or ethanol, as a solvent and employing a small quantity ofan acid catalyst, such as boron trifluoride etherate, sulfuric acid orp-toluenesulfonic acid. The reaction is generally carried out at theboiling point of the alcohol for a period of one to five hours. Anothermethod of preparing esters of Formula III will be described later.

The intermediate acid chlorides of Formula IV are generally generated bymethods well-known to those skilled in the art, such as by the reactionof the appropriate acid of Formula VI with a reagent, such as, thionylchloride in a solvent, such as benzene or toluene at the boiling pointof the solvent for a period of one to four hours. ##STR12##

The intermediate acylimiazoles can be prepared by the reaction of theappropriate carboxylic acid of Formula VI with 1,1'-carbonyldiimidazolein a solvent, such as tetrahydrofuran or dioxane at temperatures of -10°to 10° C. for periods of 15 minutes to 2 hours.

The carboxylic acid intermediates of Formula VI where A is O orO(CH₂)_(q), are designated by Formula VI-A. They are prepared by any oneof several methods: ##STR13##

The first method involves heating the ester of Formula VII, where R⁴=alkyl, in a solution of acetic acid and an aqueous inorganic acid, suchas hydrochloric acid, sulfuric acid and the like. The hydrolysis alsocan be effected in aqueous alcoholic base such as sodium hydroxide orpotassium hydroxide in aqueous methanol or ethanol. The product isrecovered by acidification with an acid, such as, hydrochloric acid. Thereaction can be carried out at temperature of 30° C. to 100° C. forperiods of about 20 minutes to 6 hours, depending on the specific esterused and the other reaction conditions. In the instances, where theester is sensitive to strong base, it is advantageous to carry out thehydrolysis using a weak base, such as aqueous sodium bicarbonate. Asolvent, such as aqueous ethanol, methanol or isopropyl alcohol is usedand the mixture heated to 45° C. to 100° C. for periods of 15 minutes to4 hours. Acidification of the reaction mixture with a strong aqueousacid, such as hydrochloric acid, hydrobromic acid or sulfuric acidproduces the desired compound of Formula VI.

A second method for the preparation of compounds of the type illustratedby Formula VI involve the reaction of a haloalkanoic orhalocycloalkanoic acid (W--A--COOH) with the appropriate phenol ofFormula VIII.

Using a haloalkanoic or halocycloalkanoic acid W--A--COOH, where W=iodo,bromo or chloro and A is as defined above, for example, iodoacetic acidor bromofluoroacetic acid, as the etherification agent, the reaction isconducted in the presence of a base. The base is selected from among thealkaline earth or alkali metal bases such as sodium or potassiumcarbonate, calcium hydroxide and the like. The reaction is carried outin a liquid reaction milieu, the choice being based on the nature of thereactants; however, solvents which are reasonably inert to the reactantsand are fairly good solvents for the compounds of Formula VIII and theW--A--COOH reagent, can be used. Highly preferable aredimethylformamide, ethanol, acetone, and N-methyl-2-pyrrolidinone andthe like.

A third method for preparing compounds of Formula VI involves thepyrolysis of the corresponding tert.-butyl ester of Formula IX. Thismethod involves heating a tert.-butyl ester of the type illustrated byFormula IX at from about 80° C. to 120° C. in a suitable nonaqueoussolvent in the presence of catalytic amount of a strong acid. Thesolvents are generally selected from among the type benzene, toluene,xylene, etc. and the acid catalyst may be a strong organic or inorganicacid, such as p-toluenesulfonic acid, benzenesulfonic acid,methanesulfonic acid, sulfuric etc. The acid, being a catalyst, isgenerally used in relatively small quantities as compared to thetert.-butyl ester, IX. It is to be noted that this reaction is apyrolysis and not a hydrolysis, since water is excluded from thereaction and the products are a carboxylic acid (Formula VI) andisobutylene and no alcohol is produced.

Another method of converting compounds of Type IX to those of Type VI isby heating compounds of Type IX with trifluoroacetic acid in a solventlike dichloromethane.

A fourth method is limited to the instances wherein A=O(CH₂)₂, whichproduces compounds of Formula VI-A. In this method, a compound ofFormula X is oxidized to a compound of Formula VI-A. ##STR14## Thereaction is conducted in a solvent mixture of water and methylenechloride (or carbon tetrachloride) using an oxidizing agent, such aspotassium permanganate and a phase transfer agent, such at "triton B"and the like.

The reaction is conducted conveniently at 10° C., but temperatures aslow as 5° C. or as high as 35° C. can be used for periods of 30 minutesto 6 hours.

The product is conveniently isolated by reducing the excess potassiumpermanganate with sodium bisulfite and hydrochloric acid, extracting theorganic phase with aqueous sodium hydroxide and acidifying the aqueousextract with an acid such as hydrochloric acid. If necessary, theproduct is purified by chromatography or recrystallization.

Compounds of formula X are prepared from the corresponding phenol ofFormula VIII by reaction with 1-bromobutene or 1-iodobutene. Thereaction (where Hal=bromo or iodo)

    VIII+Hal--CH.sub.2 CH.sub.2 CH═CH.sub.2 →X

is conveniently conducted in a polar solvent, such as dimethylformamide,1-methyl-pyrrolidone and the like. A base, such as potassium carbonateor sodium carbonate is employed to scavange the acid that is produced bythe reaction. It is often beneficial to heat the base with the phenol(VIII) for a period of 10 minutes to an hour at 90° to 100° C. togenerate the salt of the phenol before the 1-bromobutene or 1-iodobuteneis added. The final reaction is generally conducted at temperatures of50° to 100 ° C. for periods of 12 to 24 hours.

The esters of Formula VII or IX are conveniently prepared by thereaction of a phenol of Formula VIII with a haloalkanoic acid ester ofFormula W(CH₂)_(q) COOR⁴. When R⁴ is tert.-butyl, compounds of FormulaIX are produced.

    VIII+W(CH.sub.2).sub.q COOR.sup.4 →VII or IX

If lower temperatures are employed or if the particular halo ester isnot very reactive, the reaction time may be much longer.

In general, the reaction is conducted in the presence of a base, such asan alkali metal carbonate, hydroxide or alkoxide such as potassiumcarbonate, sodium carbonate, potassium hydroxide, sodium ethoxide andthe like. Solvents which are essentially inert to the reactants andproduct and in which the reactants and product are reasonably solubleare usually employed. Dimethylformamide, ethanol and acetone, forexample, have been found to be especially advantageous to use assolvents. The reaction may be conducted at a temperature in the rangefrom about 25° C. to the boiling point temperature of the particularsolvent employed. The reaction is generally complete in about 15 to 60minutes; but, the reaction may require a longer period of time.

The phenols of Formula VIII are prepared by any one of several methods;but the following method is especially convenient. This procedureinvolves the ether cleavage of anisoles of Formula XI or oxyacetic acidsof Formula VI-B. This ether cleavage is: ##STR15## accomplished by anyone of many agents known to cleave ethers, especially useful are thehydrohalide salts of weak bases, such as pyridine hydrochloride orpyridine hydrobromide, but other agents, such as aqueous hydrobromicacid, aluminum bromide or sodium nitrite in dimethylformamide can beused. When pyridine hydrohalides are used, the temperatures above thatwhich these substances melt are generally employed. This usuallyinvolves temperatures in the range of 150° to 215° C., but temperaturessomewhat lower or higher can be used. The period of heating variesdepending on the specific compound, but periods of from 15 minutes to 2hours may be used.

The anisoles of Formula XI are prepared by any one of several methodsknown to those skilled in the art; however, a convenient method consistsin the reaction of a compound of Formula XII with a compound of FormulaW--R' where W is as defined previously (iodo, bromo or chloro).##STR16##

The reaction is generally carried out by first treating the compound ofFormula XII with a suitable base, for example, an alkali metal hydride,such as sodium hydride and the like, or an alkali metal alkoxide, forexample potassium tert. butoxide and the like. The ion that is generatedis then treated with the compound of Formula W--R' (an alkyl halide,alkenyl halide or alkynyl halide). Any solvent which is substantiallyinert to the reactants employed may be used. Suitable solvents include,for example, 1,2-dimethoxyethane, tert.-butyl alcohol, benzene, toluene,dimethylformamide and the like. The reaction is conducted attemperatures in the range of 25° C. to about 125° C. In general, thereaction is conducted in the range from about 15° to 50° C. It isbeneficial to conduct the reaction in a dry, inert atmosphere, forexample in dry nitrogen or dry argon.

The carboxylic acid intermediates of Formula VI where A is a bond and Zis O═ (designated as VI-B) are prepared by the following sequence ofthree synthetic steps. ##STR17##

The 2,3-dihydro-1-oxo-1H-inden-yl trifluoromethanesulfonates of FormulaXIV are prepared from the corresponding phenols of Formula VIII. Thereaction is conducted in a polar solvent, such as dimethylformamide or1-methyl-2-pyrrolidinone in the presence of a base, such as potassiumcarbonate or sodium carbonate. The reaction is generally carried out attemperatures in the range of -10° C. to 45° C. but temperatures somewhathigher or lower can be used. The reaction time varies from 30 minutes to6 hours.

The diethyl (2,3-dihydro-1-oxo-1H-inden-yl)-malonates of Formula XV areprepared by the reaction of compounds of Formula XIV with a metal saltof diethylmalonate. The metal salt of diethyl malonate is convenientlyprepared from diethyl malonate and sodium hydride is an inert atmosphereusing a solvent, such as dimethylformamide or 1-methyl-2-pyrrolidinone.The metal salt of diethyl malonate in the solvent is then treated with acompound of Formula XIV in an inert organic solvent, for example benzeneor toluene. The reaction is generally conducted at a temperature of -5°C. to 50° C. for a period of 6 to 24 hours.

Finally, the compounds of Formula VI-B are prepared by heating compoundsof Formula XV with aqueous base. Bases, such as sodium hydroxide orpotassium hydroxide are especially useful. To achieve adequatesolubility during the reaction, an inert organic solvent is employed,such as ethanol or propanol along with the water. The reaction isgenerally conducted at temperatures in range of 50° C. to 100° C. forperiods of 2 to 24 hours. The final product (VI-B) is generated byacidification of the reaction mixture.

As mentioned earlier, the compounds of this invention possess one andsometimes two asymmetric carbon atoms. In the instances where theypossess two asymmetric carbon atoms, the reaction whereby these chiralcenters are established can produce two diastereomers. These may beseparated to obtain each pure diastereomer by methods well known tothose skilled in the art, such as by fractional crystallization, columnchromatograpy, high pressure liquid chromatography and the like.

Those compounds possessing only one asymmetric carbon atom, as well aseach pure diastereomer from compounds possessing two asymmetric carbonatoms, consist of a racemate composed of two enantiomers. The resolutionof the two enantiomers may be accomplished by forming a salt of theracemic mixture with an optically active base such as (+) or(-)amphetamine, (-)cinchonidine, dehydroabiethylamine, (+) or(-)-α-methylbenzylamine, (+) or (-)(1-naphthyl)ethylamine.(+)cinchonine, brucine, or strychnine and the like in a suitable solventsuch as methanol, ethanol, 2-propanol, benzene, acetonitrile,nitromethane, acetone and the like. There is formed in the solution, twodiastereomeric salts, one of which is usually less soluble in thesolvent than the other. Repetitive recrystallization of the crystallinesalt generally affords a pure diastereomeric salt from which is obtainedthe desired pure enantiomer. The optically pure enantiomer of thecompound of Formula I is obtained by acidification of the salt with amineral acid, isolation by filtration and recrystallization of theoptically pure antipode.

The other optically pure antipode may generally be obtained by using adifferent base to form the diastereomeric salt. It is of advantage toisolate the partially resolved acid from the filtrates of thepurification of the first diastereomeric salt and to further purify thissubstance through the use of another optically active base. It isespecially advantageous to use an optically active base for theisolation of the second enantiomer which is the antipode of the baseused for the isolation of the first enantiomer. For example, if(+)-α-methylbenzylamine was used first, then (-)-α-methylbenzylamine isused for the isolation of the second (remaining) enantiomer.

A method which is especially useful in obtaining pure enantiomersinvolving asymmetry about the 2-carbon atom is to use pure enantiomersof the intermediate compounds. This is particularly advantageous in theinstance of compounds of Formula VI, most particularly compound ofFormula VI-B. These compounds are readily resolved by the methodsdescribed above and many have already been described in the scientificand patent literature. These resolved compounds can then be used per sein subsequent synthetic steps, such as conversion to compounds of thetypes illustrated by Formula III, IV, V or VII which ultimately lead tocompounds of Formula I which are pure enantiomers.

When compounds of Formula I are prepared where both the 1-carbon atomand the 2-carbon atom of the indane ring are asymmetric, the twodiastereomers that are produced may be separated by methods well-knownto those that are skilled in the art. For example, methods such asfractional crystallization, column chromatography, high pressure liquidchromatography and the like may be used.

The instances where intermediate compounds are used which arepreresolved to the pure enantiomers in regard to the 2-carbon atom priorto establishment of the asymmetry about the 1-carbon is established areespecially advantageous. An example of this is the reduction of acompound of Formula II-B to one of Formula II-A. In this situation, twodiastereomers are produced but each consists of a single enantiomer.Thus, by using one of the methods for separating diastereomers listedabove, the two diastereomers can be separated to obtain two pureenantiomers.

Therefore, by starting with a pure enantiomer of Formula VI, two of thepossible enantiomers can be obtained. Then, by using the oppositeenantiomer of Formula VI the other two enantiomers can be obtained. Thisprovides a method of obtaining all four enantiomers of compounds ofFormula I where both the 1-carbon and 2-carbon atoms are asymmetric.

The acid addition salts of Formula I-G (where B⁺ represents a cationfrom a pharmaceutically acceptable base) are prepared by reacting acarboxylic acid of Formula I with an appropriate base of formula BH, forexample, alkali metal or alkaline earth bicarbonate, carbonate oralkoxide, an amine, ammonia, an organic quaternary ammonium hydroxide,guanidine and the like. The reaction is illustrated below: ##STR18##

The reaction is generally conducted in water when alkali metalhydroxides are used, but when alkoxides and the organic bases are used,the reaction may be conducted in an organic solvent, such as ether,ethanol, dimethylformamide and the like.

The preferred salts are the sodium, ammonium, diethanolamine,1-methylpiperazine, piperazine and the like salts.

It is to be recognized that compounds of Formula I are dibasic acids butit is generally intended to prepare only the salts derived from the moreacidic center as shown by Formula I-G. Therefore, only bases of theappropriate base strength are used to produce the monobasic salts ofFormula I-G or, alternatively, the bases are used only in amountsequivalent to the molar quantities of the acid. In the instance ofdiacidic bases, for example 1-methylpiperazine, molecular equivalentamounts of compounds of Formula I and BH are used.

Inasmuch as there are a variety of symptoms and severity associated withgrey matter edema, particularly when it is caused by head trauma stoke,cerebral hemorrhage or embolism, post-operative brain surgery trauma,spinal cord injury, cerebral infections and various brain concussions,the precise treatment is left to the practioner. Therefore, it is leftto the judgment of the practitioner to determine the patient's responseto treatment and to vary the dosages accordingly. A recommended dosagerange is from 1 microgram/kg to 20 mg/kg of body weight as a primarydose and a sustaining dose of half to equal the primary dose, every 4 to24 hours.

The compounds of this invention can be administered by a variety ofestablished methods, including intravenously, intramuscularly,subcutaneously, or orally. As with dosage, the precise mode ofadministration is left to the discretion of the practitioner. However,for the very ill and comatose patient, the parenteral route,particularly the intravenous route of administration is highlypreferred. Another advantage of the intravenous route of administrationis the speed with which therapeutic brain levels of the drug areachieved. It is of paramount importance in brain injury of the typedescribed to initiate therapy as rapidly as possible and to maintain itthrough the critical time periods. For this purpose, the intravenousadministration of drugs of the type Formula I in the form of their salts(Formula I-G) is superior.

One aspect of this invention is the treatment of persons with greymatter edema by concomitant administration of a compound of Formula I orI-G, a pharmaceutically acceptable salt, and an antiinflammatorysteroid. These steroids are of some, albeit limited, use in control ofwhite matter edema associated with ischemic stroke and head injury.Steroid therapy is given according to established practice as asupplement to the compound of Formula I or I-G as taught elsewhereherein.

Similarly, a barbiturate may be administered as a supplement totreatment with a compound of Formula I or I-G.

The compounds of Formula I or I-G are utilized by formulating them in acomposition such as tablet, capsule or elixir for oral administration.Sterile solutions or suspensions can be used for parenteraladministration. About 70 micrograms to 750 mg of a compound or mixtureof compounds of Formula I or I-G, its a physiologically acceptable salt,is compounded with a physiologically acceptable vehicle, carrier,excipient, binder, preservative, stabilizer, flavor, etc. in a dosageform as called for by accepted pharmaceutical practice. The amount ofactive substance in the composition is such that dosage in the rangeindicated is obtained.

Illustrative of the adjuvants which may be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like; a lubricant such as magnesiumstearate; a sweetening agent such as sucrose, lactose, or saccharin; aflavoring agent such as peppermint, oil of wintergreen or cherry. Whenthe dosage unit from is a capsule, it may contain in addition tomaterials of the above type a liquid carrier such as fatty oil. Variousother materials may be present as coatings or to otherwise enhance thepharmaceutical elegance of the preparation. For instance, tablets may becoated with shellac, sugar or the like. A syrup or elixir may containthe active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a conventional vehicle such as water by injection, anaturally occurring vegetable oil like sesame oil, coconut oil, peanutoil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyloleate or the like. Buffer, preservatives, antioxidants and the like canbe incorporated as required.

The basic premise for the development of agents for the treatment ofbrain injury of the types described is based on the studies inexperimental head injury by R. S. Bourke et. al. (R. S. Bourke, M. A.Daze and H. K. Kimelberg, Monograph of the International Glial Cellsymposium, Leige, Bel. Aug. 29-31, 1977 and references cited therein)and experimental stroke by J. H. Garcia et al. (J. H. Garcia, H. Kalimo,Y. Kamijyo and B. F. Trump, Virchows Archiv. [Zellopath.], 25, 191(1977).

These and other studies have shown that the primary site of traumaticbrain injury is in the grey matter where the process follows a patternof insult, edema, ischemia, hypoxia, neuronal death and necrosisfollowed, in many instances, by irreversible coma or death. Thediscovery of a drug that specifically prevents the edema would obviatethe sequalae.

Experimental head injury has been shown to produce a pathophysiologicalresponse primarily involving swelling of astroglia as a secondary,inhibitable process. At the molecular level, the sequence appears to be:trauma, elevation of extracellular K⁺ and/or release ofneurotransmitters, edema, hypoxia and necrosis. Astroglial swellingresults directly from A K⁺ -dependent, cation-coupled, chloridetransport from the extracellular into the intracellular compartment witha concommitant movement of an osmotic equivalent of water. Thus, anagent that specifically blocks chloride transport in the astroglia isexpected to block the edema caused by trauma and other insults to thebrain. It is also important that such chloride transport inhibitors befree or relatively free of side effects, particularly thosecharacteristics of many chloride transport inhibitors, such as diureticproperties. Compounds of the type illustrated by Formula I and I-Gexhibit the desired effects on brain edema and are relative free ofrenal effects.

That this approach is valid has been demonstrated by the correlation ofthe in vitro astroglial edema inhibiting effects of chloride transportinhibitors with their ability to reduce the mortality of animalsreceiving experimental in vivo head injury. As a final proof, onecompound (ethacrynic acid) which exhibited activity both in vitro and invivo assays was effective in reducing mortality in clinical cases ofhead injury. These studies are described in the Journal of MedicinalChemistry, Volume 18, page 567 (1982).

Three major biological assays can be used to demonstrate biologicalactivity of the compounds. The (1) in vitro cat cerebrocortical tissueslice assay, (2) the in vitro primary rat astrocyte culture assay and(3) the in vivo cat head injury assay. The first assay, the in vitro catcerebrocortical tissue slice assay has been described by Marshall, L.F.; Shapiro, H. M.; Smith, R. W. In "Seminars in Neurological Surgery:Neural Trauma"; Popp, A. J.; Bourke, R. S.; Nelson, L. R.; Kimelberg, H.K., Eds.; Raven Press: New York, 1979; p. 347, by Bourke, R. S.;Kimelberg, H. K.; Daze, M. A. in Brain Res. 1978, 154, 196, and byBourke, R. S.; Kimelberg, H. K.; Nelson, L. R. in Brain Res. 1976, 105,309. This method constitutes a rapid and accurate method of determiningthe intrinsic chloride inhibitory properties of the compounds of theinvention in the target tissue.

The second assay method involves the in vitro primary rat astrocyteassay. The method has been described by Kimelberg, H. K.; Biddlecome,S.; Bourke, R. S. in Brain Res. 1979, 173, 111, by Kimelberg, H. K.;Bowman, c.; Biddlecome, S.; Bourke, R. S., in Brain Res. 1979, 177, 533,and by Kimelberg, H. K.; Hirata, H. in Soc. Neurosci. Abstr. 1981, 7,698. This method is used to confirm the chloride transport inhibitingproperties of the compounds in the pure target cells, the astrocytes.

The third assay method, the in vivo cat head injury assay has beendescribed by Nelson, L. R.; Bourke, R. S.; Popp, A. J.; Cragoe, E. J.Jr.; Signorelli, A.; Foster, V. V.; Creel, in Marshall, L. F.; Shapiro,H. M.; Smith, R. W. In "Seminars in Neurological Surgery: NeuralTrauma"; Popp, A. J.; Bourke, R. S.; Nelson, L. R.; Kimelberg, H. K.,Eds.; Raven Press: New York, 1979; p. 297.

This assay consists of a highly relevant brain injury in cats which isachieved by the delivery of rapid repetitive acceleration-decelerationimpulses to the animal's head followed by exposure of the animals to aperiod of hypoxia. The experimental conditions of the assay can beadjusted so that the mortality of the control animals falls in the rangeof about 25 to 75%. Then, the effect of the administration of compoundsof this invention in reducing the mortality over that of the controlanimals in concurrent experiments can be demonstrated.

Using the assays described supra, compounds of this invention exhibitmarked activity both in vitro and in vivo. For example, in the in vitroassays compounds of Formula I and I-G inhibit chloride transport by 50%at concentrations as low as 10⁻⁹ to 10⁻¹⁰ molar and lower. Likewise inthe in vivo assay compound of Formula I or I-G reduce the mortality dueto head injury by statistically significant values as compared tocontrol animals.

The following examples are included to illustrate the preparation ofrepresentative compounds of Formula I and I-G and representative dosageforms of these compounds.

EXAMPLE 1(+)3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A:(+)-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)Trifluoromethane-sulfonate

A mixture of(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one(25.05 g, 0.0837 mole) and potassium carbonate (35.4 g. 0.256 mole) indimethylformamide (100 ml.) is stirred at 25° C. for 1 hour, cooled to0° C. then treated with trifluoromethanesulfonyl chloride (10.5 ml.,0.984 mole) over a 3 minute period. The reaction mixture is stirred at25° C. for 1 hour, poured into ice water (700 ml.) extracted with ether,washed with water and brine and dried over MgSO₄. The ether isevaporated at reduced pressure to give 34.2 g of (+)(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate which melts at 104°-6° C. and is used in StepB without further purification.

Step B:(+)-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticAcid

Diethyl malonate (34.4 g., 0.215 mole) is added to a stirred suspensionof sodium hydride (56% on mineral oil, 9.2 g., 0.215 mole) indimethylformamide (130 ml.) at 10°-15° C. in an inert atmosphere duringa 1 hour period. The reaction mixture is stirred at 25° C. for 1.5hours, cooled to 5° C. and treated with(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate 34.2 g., 0.0793 mole) in toluene (45 ml.) overa 1 hour period 5°-7° C. The reaction mixture is stirred at 25° C. for18 hours, poured into a mixture of ice water (700 ml.) and concentratedhydrochloric acid (20 ml.), extracted with ether (3×125 ml.) andmethylene chloride (125 ml.). The combined organic extracts are washedwith water and brine and dried over MgSO₄.

Evaporation of the organic solvents at reduced pressure gives crude(+)-diethyl(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)malonatewhich is dissolved in ethanol (100 ml), treated with a solution ofsodium hydroxide (40 g) in water (300 ml.) and heated at reflux for 4hours. The reaction mixture is cooled, diluted with water (300 ml) andextracted with hexane (2×125 ml).

The aqueous layer is acidified with hydrochloric acid, extracted withether (4×100 ml) then extracted into aqueous sodium bicarbonate (15×100ml) which is acidified with hydrochloric acid and extracted with etherand methylene chloride. The combined organic extracts are washed withwater and brine, dried over MgSO₄ and evaporated at reduced pressure togive 23 g. of(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid. A small sample is converted to its dicyclohexylamine salt, m.p.,163° C.

Analysis for C₁₇ H₁₈ Cl₂ O₃.C₁₂ H₂₃ N; Calc. C, 66.66; H, 7.91; N, 2.68;Found: C, 66.15; H, 8.17; N, 2.71%.

Step C:(+)-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide

To a solution of(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid (21.8 g., 0.0623 mole) in chloroform (150 ml) and dimethylformamide(1 drop) is added thionyl chloride (25 ml). The reaction mixture isheated at reflux for 3 hours, cooled and concentrated at reducedpressure. The crude(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetylchloride, thus obtained, is dissolved in methylene chloride (75 ml) andadded over 0.5 hour to a mixture of ether (100) ml) and methylenechloride (75 ml) which has been saturated with ammonia.

The addition is conducted at 0°-10° C. Ammonia is passed into thesolution for 15 minutes following the addition and then concentratedaqueous ammonia (25 ml) and water (150 ml) are added. The organic layeris washed with water, brine, dried over MgSO₄ and evaporated at reducedpressure leaving 19.8 g of(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideas a foam which is used in Step D without further purification.

Step D:(+)3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine salt

In a nitrogen atmosphere,(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide(19.8 g., 0.0582 mole) and diethyl oxalate (9.14 g., 0.626 mole) aredissolved in dimethylformamide (100 ml.) and stirred in an ice bath.Potassium tert. butoxide (15.2 g, 0.136 mole) is added in two portionsat a 10 minute interval. The reaction mixture is stirred at 25° C. for18 hours, poured into water (600 ml) acidified with hydrochloric acid,extracted with ether, washed with water and brine and dried over MgSO₄.Evaporation of the ether at reduced pressure gives(+)3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneas the hemietherate in the form of a foam. Upon drying at reducedpressure, the analysis of the hemietherate is as follows:

Calc. for C₁₉ H₁₇ Cl₂ NO₄.1/2C₄ H₁₀ O: C, 58.48; N, 5.14; N, 3.25;Found: C, 58.61; H, 4.91; N, 3.45%.

Further drying of the hemietherate at reduced pressure at about 70° C.gives the solvent free material.

The 1-methylpiperazine salt of the above described compound is preparedby dissolving the compound in ether and treating it with an equimolarquantity of 1-methylpiperazine which gives a precipitate which uponfiltration and drying weighs 25.2 g. After recrystallization from2-propanol this salt melts at 204°-206° C., [α]²⁵ D=+21.7° (C=1, CH₃OH).

Analysis, calculated for C₁₉ H₁₇ Cl₂ NO₄.C₅ H₁₂ N₂ ; C, 58.30; H, 5.91;N, 8.50; Found: C, 58.05; H, 5.98; N, 8.67%.

EXAMPLE 2(+)3-(6,7-Dichloro-2-cyclopentyl-2-ethyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine salt

The preparation is conducted essentially as described in Example 1,Steps A through D except that an equimolar amount of6,7-dichloro-2-cyclopentyl-2-ethyl-2,3-dihydro-5-hydroxy-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step so that3-(6,7-dichloro-2-cyclopentyl-2-ethyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 33-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

By following substantially the procedure described in Example 1, Steps Ato D, but substituting an equimolar amount of2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-onefor the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A and using the product of each step in thesubsequent step there are obtained3-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

Analysis for C₂₂ H₂₃ Cl₂ NO₄ ; Calc. C, 60.55; H, 5.31; N, 3.23; Found:C, 60.56; H, 5.60; N, 3.10%.

EXAMPLE 43-(6,7-Dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is conducted essentially as described in Example 1,Steps A through D except that an equimolecular amount of6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(1-methylethyl)-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then the product of Steps A, B and C are usedin each subsequent step so that3-(6,7-dichloro-2,3-dihydro-1-oxo-methyl-2-(1-methylethyl)-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 53-(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneStep A:6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-one

6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-1H-inden-1-one(56.7 g., 0.181 mole) dissolved in dry toluene (200 ml.) is addeddropwise with stirring under nitrogen over 1 hour at room temperature toa suspension of sodium hydride (56% in mineral oil, 8.74 g. 0.204 mole)in toluene (50 ml) and dry dimethylformamide (220 ml.) The mixture isstirred at room temperature for 1.75 hours after completion of theaddition, cooled to 0° C., and then methyl iodide (25 ml., 0.4 mole) isadded at 0°-5° C. After stirring at 5° for 25 minutes and for one hourat room temperature, methanol (15 ml.) is slowly added followed byacetic acid (10 ml.). The mixture is poured into ice water (1500 ml.)the layers are separated and the aqueous phase extracted three timeswith toluene (150 ml.) and then with methylene chloride (150 ml.). Thecombined organic extracts are washed with water, dried over magnesiumsulfate and concentrated under vacuum. The residue is triturated with amixture of hexane and petroleum ether (1:1) are filtered. The solid (50g.) is recrystallized from a mixture of methylcyclohexane (110 ml.) andhexane (55 ml.) to obtain 38 g. of product, m.p. 75°-77° C. Thefiltrates from the recrystallization are concentrated and the residuerecrystallized from methylcyclohexane to obtain a second drop of 5.5 g.for a total yield of 73%.

Step B:6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one

6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-one(43.5 g., 0.1329 mole) is added to fused pyridine hydrochloride (440 g.)at 160° C. the mixture is heated with stirring under nitrogen at aninternal temperature of 175°-185° C. for 80 minutes. The molten mixtureis poured into ice and water (1500 ml.). The solid is extracted withmethylene chloride and then ether. The combined organic extracts arewashed with water, dried over magnesium sulfate and concentrated invacuo. The filtrate is further concentrated to obtain an additional 7.0g. of6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one,m.p. 188°-90° for a total yield of 96%.

Step C:(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)Trifluoromethanesulfonate

Anhydrous potassium carbonate (17.7 g., 0.128 mole) is added to asolution of6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one(13.35 g., 0.0426 mole) in dry dimethylformamide (60 ml.) The suspensionis stirred for 1 hour at room temperature, cooled to 15° C. and thentrifluoromethanesulfonyl chloride is added at 15°-18° C. After stirringfor 1 hour at room temperature, the reaction mixture is poured into icewater (700 ml.). The oil that separates is extracted with ether (125ml.). The combined organic extracts are washed with water, dried overmagnesium sulfate and concentrated in vacuo to obtain the amber, oilyproduct (18.8 g.), which is used in the next step without furtherpurification.

Step D:(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid

Diethyl malonate (18.3 g., 0.114 mole) is added with stirring undernitrogen at 10°-15° C. to a suspension of sodium hydride (56% in mineraloil, 4.89 g., 0.114 mole) in dry dimethylformamide (85 ml.). Thereaction mixture is stirred for 1 hour at room temperature, cooled to 5°C. and then6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yltrifluoromethanesulfonate (18.8 g., 0.0426 mole dissolved in dry toluene(20 ml.) is added over 1 hour at 5°-7° C. After stirring at roomtemperature for 18 hours, the reaction mixture is poured into ice water(1000 ml.) and extracted with ether (4×150 ml.) and then with methylenechloride (2×50 ml.). The combined organic extracts are washed threetimes with water and concentrated under vacuum. The residual oil isdissolved in ethanol (150 ml.) and added to a solution of 20 g. ofsodium hydroxide in water (150 ml.). The mixture is refluxed for 3hours, cooled and the ethanol removed under vacuum. The residue isdiluted with water, extracted with hexane and then acidified withhydrochloric acid. The gum that separates is extracted with ether. Thecombined etheral extracts are washed with water and then extractedrepeatedly with dilute sodium bicarbonate. The combined aqueous extractsare acidified with hydrochloric acid and extracted with ether. The etherextracts are washed with brine, dried over magnesium sulfate anconcentrated under vacuum to obtain the crude(6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid, 9.3 g., m.p. 145.5°-148° C., in 62% yield. Recrystallization frombutyl chloride affords material which melts at 149°-151° C.

Calc. for C₁₈ H₂₀ Cl₂ O₃ : C, 60.85; H, 5.67; Found: C, 60.86; H, 6.02.

Step E:(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-yl)acetamide

To(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid (5.68 g., 0.016 mole) dissolved in chloroform (25 ml.) containingdimethylformamide (1 drop), thionyl chloride 92.4 ml., 0.33 mole) isadded. The mixture is refluxed for 16 hours, cooled, concentrated undervacuum and the residual acid chloride dissolved in methylene chloride(25 ml.). The solution is added over 10 minutes with stirring andcooling in an ice bath to a solution of ether (200 ml.) which had beensaturated with ammonia. The mixture is stirred an additional 10 minutesand then poured into ice water. The layers are separated and the aqueousphase extracted with ether and then with methylene chloride. Thecombined organic extracts are washed with brine, dried over magnesiumsulfate and concentrated under vacuum to obtain the(6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide,5.0 g., 88%, as an orange colored foam which is used in the next stepwithout further purification.

Step F:3-(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide(5 g., 0.0141 mole) and diethyl oxalate (2.19 g., 0.015 mole) aredissolved in dry dimethylformamide (30 ml.) and stirred in an ice bathunder nitrogen for 20 minutes. Potassium t-butoxide (3.53 g., 0.0315mole) is then added in two portions 15 minutes apart. The mixture isstirred while cooling in the ice bath for another 45 minutes, thenstirred at room temperature for 18 hours and poured into ice water (500ml.) The mixture is acidified with hydrochloric acid and extracted withether (4×125 ml.). The combined organic extracts are washed with waterand then repeatedly extracted with dilute sodium carbonate. The combinedaqueous extracts are acidified with hydrochloric acid, extracted withmethylene chloride and then with ether. The combined organic extractsare washed with water, dried over magnesium sulfate and concentratedunder vacuum. The residue is chromatographed on silica (175 g.) with amixture of toluene, dioxane and acetic acid (50:5:1). The appropriateproduct fractions are concentrated under vacuum and the residue isdissolved in ether and extracted with dilute sodium bicarbonate. Theaqueous extracts are acidified with hydrochloric acid and extracted withmethylene chloride and then with ether. The combined organic extractsare washed with water, dried over magnesium sulfate and concentratedunder vacuum to obtain the3-(6,7-Dichloro-2-cyclopentylmethyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as a foamwhich was then dried under high vacuum at 90° C. for 2 hours to give 3.6g. (63%).

Calculated for C₂₀ H₁₀ Cl₂ NO₄ : C, 58.85; H, 4.69; N, 3.43; Found: C,58.90; H, 4.98; N, 3.20.

EXAMPLE 63-(2-Allyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out essentially as described in Example 1,Steps A through D, except that an equimolar amount of2-allyl-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one issubstituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step so that3-(2-allyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt is obtained in Step D.

EXAMPLE 73-(6,7-dichloro-2,3-dihydro-1-oxo-phenyl-2-propargyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

Step A:6,7-dichloro-2,3-dihydro-5-hydroxy-2-phenyl-2-propargyl-1H-inden-1-one

The preparation is conducted essentially as described in Example 5, StepB except that an equimolar amount of[(6,7-dichloro-2,3-dihydro-1-oxo-2-phenyl-2-propargyl-1H-inden-5-yl)oxy]aceticacid is used in place of the6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-oneused in Example 5, Step B. There is thus obtained6,7-dichloro-2,3-dihydro-5-hydroxy-2-phenyl-2-propargyl-1H-inden-1-one.

Steps B, C, D and E:

3-(6,7-dichloro-2,3-dihydro-1-oxo-2-phenyl-2-propargyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The synthesis was carried out essentially as described in Example 1,Steps A through D except that an equimolar amount of6,7-dichloro-2,3-dihydro-5-hydroxy-2-phenyl-2-propargyl-1H-inden-1-onewas used in place of the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then the products of Steps B, C and D areused in each subsequent step so that3-(6,7-dichloro-2,3-dihydro-1-oxo-2-phenyl-2-propargyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione1-methyl-piperazine salt is obtained in Step E.

EXAMPLE 83-(6,7-Dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione1-Methylethanolate

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Steps A through D, except that an equimolaramount of6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-phenyl-1H-inden-1-one issubstituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-indene-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step so that3-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione1-methylethanolate is obtained in Step D. This product melts at140°-144° C. after recrystallization from 1-methylethanol.

Analysis Calculated for C₂₀ H₁₃ Cl₂ NO₄.C₃ H₈ O: N, 3.03; H, 4.58; Cl,15.34; Found: N, 3.02; H, 4.46, Cl, 15.26%.

EXAMPLE 93-(2-Benzyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Hemietherate

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Steps A through D, except that an equimolaramount of2-benzyl-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one issubstituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step so that3-(2-benzyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt hemietherate are obtained in Step D.

Analysis calculated for C₂₁ H₁₅ Cl₂ NO₄.C₅ H₁₂ N₂.1/2C₄ H₁₀ O: C, 60.76;H, 5.83; N, 7.59; Found: C, 60.54; H, 6.00; N. 7.56%.

EXAMPLE 103-(6,7-Dichloro-2-p-fluorophenyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine salt

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Steps A through D, except that an equimolaramount of6,7-dichloro-2-p-fluorophenyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1, and Step A. Then, the product of Steps A, Band C are used in each subsequent step so that3-(6,7-dichloro-2-p-fluorophenyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 113-(6,7-Dichloro-2,3-dihydro-2-p-methoxyphenyl-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine salt

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Steps A through D, except that an equimolaramount of(6,7-Dichloro-2,3-dihydro-2-p-methoxyphenyl-2-methyl-1-oxo-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1, Step A. Then, the product of Steps A, B and Care used in each subsequent step (i.e. Steps B, C and D respectively) sothat3-(6,7-dichloro-2,3-dihydro-2-p-methoxyphenyl-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 123-[6,7-Dichloro-2,3-dihydro-1-oxo-2-methyl-2-(2-thienyl)-1H-inden-5-yl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out by following essentially the proceduresdescribed in Example 1, Steps a through D, except that an equimolaramount of6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(2-thienyl)-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1, Step A. Then, the product of Steps A, B and Care used in each subsequent step (i.e. Steps B, C and D respectively) sothat3-[6,7-dichloro-2,3-dihydro-1-oxo-2-methyl-2-(2-thienyl)-1H-inden-5-yl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 133-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dioneHemitoluene Solvate and Their (+)-Diastereomers

A stirred solution of a mixture of the diastereomeric racemates of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dione(2.55 g., 0.0062 mole) in acetone (75 ml.) is treated with a solution ofJones reagent (prepared from CrO₃ (0.91 g.) H₂ O (6.5 ml.) and H₂ SO₄(0.8, SO₄ (0.8 ml.)) over a 10 minute period. The acetone solution isdecanted from the precipitated salts, evaporated at reduced pressure,poured into water (100 ml.) and extracted with ether which, in turn, iswashed with water, dried over MgSO₄ and evaporated at reduced pressure.The resultant oil is chromatographed on silica (75 g.) eluted with amixture of methylene chloride, tetrahydrofuran and acetic acid (50:1:1).The pertinent fractions are evaporated at reduced pressure, the residuetreated with toluene (100 ml.) and evaporated to azeotrope the residualacetic acid to provide3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dionehemitoluene solvate which melts at 181°-3° C.

Analysis calculated for C₁₉ H₁₇ Cl₂ NO₅.1/2C₇ H₈ ; N, 3.07; H, 4.64; Cl,15.54; Found: N, 2.96; H, 4.78; Cl, 15.47%.

By starting with a mixture of the two (+)-diastereomers of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dioneinstead of the mixture of racemates described above there is obtained(+)3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1oxo-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dione.

EXAMPLE 143-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxymethyl]-4-hydroxy-1H-pyrrole-2,5-dione1-Methylpiperazine Salt Step A:4-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-1-butene

2-Cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-5-hydroxy-1H-inden-1-one(12 gm., 0.04 mole) is dissolved in dimethylformamide (30 m.) andtreated with potassium carbonate (5.5 gm., 0.04 mole). The mixture isstirred and heated on a steam bath for 30 minutes and 4-bromo-1-butene(5.5 gm., 0.04 mole) is added and the mixture stirred and heated at 60°C. for 24 hours. The reaction mixture is poured into water (300 ml.)and, after standing, the product removed by filtration, dried andrecrystallized from petroleum ether. The yield is 11.5 gm., m.p. 63°-65°C.

Analysis Calc. C₁₉ H₂₂ Cl₂ O₄ : C, 64.59; H, 6.28: Found: C, 64.72; H,6.46%.

Step B:4-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl-oxy)]propanoicacid

A mixture of4-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-1-butene8.8 gm., 0.025 mole), water (200 ml.), methylene chloride (100 ml.),potassium permanganate (9.9 gm, 0.062 mole) and "triton B" (300 mg.) isstirred at 10° C. for 2 hours. Sodium bisulfite and concentratedhydrochloric acid is added portionwise alternately until a clearsolution results. The methylene chloride phase is separated, washed withwater and then extracted with 5% sodium hydroxide solution. The aqueousextract is separated and acidified and then extracted with ether. Theether extract is dried over sodium sulfate and the solvent removed usinga rotary evaporator. The oily product is chromatographed using a columnof silica gel (300 gm.) using a mixture of methanol and toluene (1:4,Vol./Vol.). Evaporation of pooled cuts of uniform composition gives 2.1gm. of an oil which solidifies upon trituration with petroleum ether.Recrystallization from a mixture of ether (30 ml.) and petroleum ether(60 ml.) gives pure product m.p. 140°-142° C.

Analysis Calc. for C₁₈ H₂₀ Cl₂ O₄ : C, 58.23; H, 5.43%: Found: C, 58.33;H, 5.60%.

Step C:3-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]propanamide

The reaction is carried out as described in Example 1, Step C exceptthat the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticis replaced by an equimolar amount of3-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-1H-inden-5-yl)oxy]propanoicacid. There is thus obtained first3-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-1H-inden-5-yl)oxy]propanoylchloride and, finally,3-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-1H-inden-5-yl)oxy]propanamide.

Step D:3-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxymethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The reaction is conducted as described in Example 1, Step D except thatthe(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideis replaced by an equimolar amount of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]propanamide.There is thus obtained3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxymethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 153-[2-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A:4-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramide

A stirred solution of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyricacid (7 g.,) and boron trifluorideetherate (5 ml.) in methanol (50 ml.)is heated at reflux for 1 hour. The methanol is evaporated at reducedpressure, the residue dissolved in ether, washed with water, dried overMgSO₄ and evaporated at reduced pressure. The crude methyl ester thusobtained is dissolved in dimethylformamide (25 ml.), treated withmethanol saturated with ammonia and stirred at 25° C. for 2 weeks. The4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramideis separated as white crystals melting at 138° C. and is used in Step Bwithout further purification.

The4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramideis also prepared by treating a solution of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyricacid (3.85 g., 0.01 mole) in dry tetrahydrofuran (100 ml.) with1,1'-carbonyldiimidazole (1.62 g., 0.01 mole) in tetrahydrofuran (25 ml)at 0° C., stirring for one hour and then treating with 25% aqueousammonia (25 ml), stirring for 4 hours at 35° C., and removing thesolvent to obtain the product.

Step B:3-[2-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

To a stirred solution of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramide(1.83 g., 4.8 mmole) and diethyl oxalate (0.7 ml., 5.2 mmole) cooled inan ice bath and in a nitrogen atmosphere is added potassium tert.butoxide (1.24 g., 11.1 mmole) in several portions during a 10 minuteperiod. The reaction mixture is stirred at 25° C. overnight, poured intocold aqueous hydrochloric acid, extracted into ether, extracted into 2%potassium hydroxide, acidified with aqueous hydrochloric acid, extractedinto ether, washed with water, dried over MgSO₄ and evaporated atreduced pressure. The residue is chromatographed on silica (40 g.,) andeluted with a mixture of methylene chloride, tetrahydrofuran and aceticacid (50:1:1). The pertinent fractions are evaporated at reducedpressure, the residue treated with toluene (50 ml) and evaporated toazeotrope the residual acetic acid. The residual oil is dissolved inether (10 ml.) and methanol (0.5 ml.) then treated with1-methylpiperazine to give3-2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione1-methylpiperazine salt which melts at 191° C.

Analysis for C₂₁ H₂₁ Cl₂ NO₅.C₅ H₁₂ N₂ : Calc: C, 57.99; H, 6.18: N,7.80; Found: C, 58.44; H, 6.56; N, 7.73%.

EXAMPLE 163-[3-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)propyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A: Methyl5-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoate

2-Cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-hydroxy-1H-inden-1-one(12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.) andtreated with potassium carbonate (5.5 g., 0.04 mole). Methyl5-bromopentanoate (8.5 g., 0.04 mole) is added dropwise with goodstirring over a period of 30 minutes. Then, the mixture is stirred andheated in a steam bath for two hours. The mixture is cooled and pouredin to ice water (300 ml.). The product which solidifies upon standing isremoved by filtration. The yield is 15.1 g., m.p. 83°-86° C. Uponrecrystallization from petroleum ether the methyl5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoatemelts at 85°-88° C.

Analysis: Calculated for C₂₁ H₂₆ Cl₂ O₄ : C, 61.02; H, 6.34: Found: C,61.26; H, 6.64%.

Step B:5-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoicacid

A mixture of methyl5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoate(14 g., 0.0339 mole), acetic acid (100 ml) and 6N hydrochloric acid (50ml) is stirred and refluxed for 6 hours. The mixture is poured intowater (400 ml) and the product which solidifies upon standing is removedby filtration and dried. The product is recrystallized from a mixture oftetrahydrofuran, ether and petroleum ether (50/100/200 ml) to give 12.5g, of5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)]pentanoicacid, m.p. 106°-108° C.

Analysis calculated for C₂₀ H₂₄ Cl₂ O₄ : C, 60.15; H, 6.06; Found: C,60.19; H, 6.23%.

Steps C and D

These steps are carried out by following essentially the proceduresdescribed in Example 1, Steps C and D except that an equimolar amount of5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoicacid is substituted for(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid that is used in Example 1, Step C. Thus, there is obtained in StepC5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanamideand in Step D,3-[3-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)propyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 173-[4-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)butyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A: Ethyl6[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate

6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one(12 g., 0.04 mole) is dissolved in dimethylformamide (50 ml.), treatedwith potassium carbonate (5.5 g., 0.04 mole) and heated and stirred on asteam bath for 30 minutes. Ethyl 6-bromohexanoate (8.9 g., 0.04 mole) isadded dropwise with good stirring over 15 minutes, then the mixture isheated and stirred in a steam bath for two hours. The reaction mixtureis poured into water (400 ml.) and extracted with ether (2×150 ml.) Theeither extract is dried over sodium sulfate, filtered and the etherremoved at reduced pressure. The residue, which crystallizes uponstanding, is recrystallized from a mixture of ether and petroleum etherto give ethyl6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate,16 g., m.p. 69°-72° C.

Analysis, calculated for C₂₃ H₃₀ H₃₀ Cl₂ O₄ : C, 62.58; H, 6.85. Found:C, 62.78; H, 7.11%.

Step B:6-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoicacid

A mixture of ethyl6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate(16 g., 0.036 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50ml.) is stirred and refluxed for 6 hours. The mixture is poured into icewater (500 g.), extracted with ether, dried over Na₂ SO₄, filtered andconcentrated to a volume of 100 ml., and chilled. A total of 11.5 of6-[6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoicacid separates, m.p. 127°-129° C.

Analysis, calculated for C₂₁ H₂₆ Cl₂ O₄ : C, 61.01; H, 6.34; Found: C,61.03; H, 6.54%.

Steps C and D

These steps are carried out by following essentially the proceduresdescribed in Example 1, Steps C and D except that an equimolar amount of6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoicacid is substituted for(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid that is used in Example 1, Step C. Thus, there is obtained in StepC6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanamideand in Step D,3-[4-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)butyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 183-[5-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)pentyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A: Ethyl7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate

6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one(12 g., 0.04 mole) is dissolved in dimethylformamide (30 ml.), andpotassium carbonate (5.5 g., 0.04 mole) is added and the mixture stirredand heated on a steam bath for 30 minutes. Ethyl 7-bromoheptanoate isadded dropwise over 10 minutes with stirring and heating on a steam bathfor two hours. The mixture is poured into a mixture of ice and water(300 g., total) and then extracted with ether. The ether extract isdried over Na₂ SO₄, filtered and the ether removed at reduced pressure.The residue is dissolved in petroleum ether and cooled to -70° C. toobtain ethyl7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate,17.7 g., m.p. 47°-50° C.

Analysis, calculated for C₂₄ H₃₂ Cl₂ O₄ : C, 63.29; H, 7.08; Found: C,63.42; H, 7.35%.

Step B:7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoicacid

A mixture of ethyl7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate(16 g., 0.035 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50ml.) is stirred and refluxed for 6 hours. The mixture is poured intowater (400 ml.) where upon the product slowly solidifies. The product isremoved by filtration, dried and recrystallized from a mixture oftetrahydrofuran, ether and petroleum ether (50, 100 and 200 ml.,respectively) to give7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoicacid, 12.1 g., m.p. 107°-110° C.

Analysis, calculated for C₂₂ H₂₈ Cl₂ O₄ : C, 61.83; H, 6.60; Found: C,61.93; H, 6.90%.

Steps C and D

These steps ar carried out by following essentially the proceduresdescribed in Example 1, Steps C and D except that an equimolar amount of7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoicacid, is substituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid used in Step C. Thus, there is obtained in Step C,7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanamideand in Step D,3-[5-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)pentyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 193-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A:(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide

To a stirred solution of(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide(6.8 g., 0.02 mole) in ethanol (100 ml) is added sodium borohydride (760mg. 0.02 mole). After one hour another portion of sodium borohydride(760 mg, 0.021 mole) is added and stirring continued for 3 hours. Thereaction mixture is poured into ice water and extracted with ethylacetate. The ethyl acetate extract is washed with water and dried overmagnesium sulfate. The ethyl acetate is evaporated at reduced pressureto give(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamideconsisting of a mixture of two diastereomer, each of which is aracemate.

Step B:3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

In an atmosphere of dry nitrogen,(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide(7.8 g., 0.02 mole) diethyl oxalate (3.14 g., 0.0214 mole) anddimethylformamide (40 ml.) is stirred while cooling in an ice bath.Potassium tert.-butoxide (5.2 g., 0.046 mole) is added in two portionsat 10 minute intervals. The mixture is then stirred at 25° C. for 18hours, poured into water, acidified with hydrochloric acid, extractedinto ether and the ether extract dried over magnesium sulfate.Evaporation of the ether at reduced pressure gives3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-yl)-4-hydroxy-1H-pyrrole-2,5-dioneas a mixture of two diastereomers. The mixture of two diastereomers isconverted to its 1-methylpiperazine salt, m.p. 226-8.

Analysis, calculated for C₁₉ H₁₉ Cl₂ O₄.C₅ H₁₂ N₂ : C, 58.07; H, 6.29;N, 8.46; Found: C, 57.89; H, 6.40; N, 8.47; (which are separated bychromatography to two pure racemates designated as α-racemate andβ-racemate).

EXAMPLE 203-[2-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione

The preparation is carried out by following substantially the proceduresdescribed in Example 19, Steps A and B but substituting an equimolaramount of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1H-inden-5-yl)oxy]butyramide(Example 15, Step A) is substituted for the(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideused in Example 19, Step A. Then, the product of Step A is used in StepB to obtain3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneas a mixture of two diastereomers each consisting of a racemate whichare separated by chromatography to give the two pure racematesdesignated as α-racemate and β-racemate.

EXAMPLE 213-(7-Chloro-2-cyclopentyl-2,3-dihydro-2,6-dimethyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Steps A and D except that an equimolar amount of7-chloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2,6-dimethyl-1H-inden-1-oneis substituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step (i.e., Steps B, C and D respectively) sothat3-(7-chloro-2-cyclopentyl-2,3-dihydro-2,6-dimethyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 223-(2-Cyclopentyl-2,3-dihydro-2,6,7-trimethyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out by following essentially the proceduresdescribed in Example 1, Steps A and D except that an equimolar amount of2-cyclopentyl-2,3-dihydro-5-hydroxy-2,6,7-trimethyl-1H-inden-1-one issubstituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step (i.e., Steps B, C and D respectively) sothat3-(2-cyclopentyl-2,3-dihydro-2,6,7-trimethyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 23(-)-3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out by following substantially described inExample 1, Steps A and D substituting an equimolar amount of(-)6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the product of Steps A, B and C areused in each subsequent step so that(-)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D. The meltingpoint of the 1-methylpiperazine salt is 203°-204° C.

Analysis, calculated C₂₄ H₂₉ Cl₂ N₃ O₄ : C, 58.30; H, 5.91; N, 8.50%.Found: C, 58.37; H, 6.02; N, 8.61%

EXAMPLE 24(+)-[6,7-Dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A:(+)6,7-Dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-1-one

The preparation is conducted essentially as described in Example 5, StepB except that an equimolar amount of(+)(6,7-dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl)-aceticacid is substituted for the6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-onethat is used in Example 5, Step B. There is thus obtained in(+)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(1-methylethyl)-1H-inden-1-one.

Steps B, C, D and E

The synthesis is carried out essentially as described in Example 1,Steps A through D except that an equimolar amount of(+)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(1-methylethyl)-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1, Step A. Then, the products of Step B, C and Dare used in each subsequent step (i.e., Steps C, D and E) so that(+)-6,7-dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione-1methylpiperazine salt is obtained in Step E.

EXAMPLE 25 (-)[6,7-Dichloro2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt Step A: (-)[6,7-Dichloro2,3-dihydro-2-methyl-5-hydroxy-2-(1-methylethyl)]-1H-inden-1-one

The preparation is carried out essentially as described in Example 5,Step B except that an equimolar amount of(-)[(6,7-dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl)oxy]aceticacid is substituted for the6,7-dichloro-2-cyclopentylmethyl-2,3-dihydro-5-methoxy-2-methyl-1H-inden-1-onethat is used in Example 5, Step B. There is thus obtained(-)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(1-methylethyl)-1H-inden-1-one.

Steps B, C, D

These synthetic steps are carried out essentially as described inExample 1, Steps A through D except that an equimolar amount of(-)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-(1-methylethyl)-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the products of step B, C and D areused in each subsequent step (i.e., Steps C and D) so that(-)-[6,7-dichloro-2,3-dihydro-2-methyl-2-(1-methylethyl)-1-oxo-1H-inden-5-yl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 26(+)-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is conducted essentially as described in Example 1,Steps A though D except that(+)-2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the products of Step A, B and C areused in each subsequent step (i.e., Steps B, C and D) so that(+)-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 27(-)-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is conducted essentially as described in Example 1,Steps A though D except that(-)-2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-oneused in Example 1, Step A. Then, the products of Step A, B and C areused in each subsequent step (i.e., Steps B, C and D) so that(-)-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 28(+)-(6,7-Dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out substantially as described in Example 1,Steps A though D except that(+)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-phenyl-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1, Step A. Then, the products of Step A, B and Care used in each subsequent step (i.e., Steps B, C and D) so that(+)-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 29(-)-(6,7-Dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out substantially as described in Example 1,Steps A through D except that(-)-6,7-dichloro-2,3-dihydro-5-hydroxy-2-methyl-2-phenyl-1H-inden-1-oneis substituted for the(+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-onethat is used in Example 1. Step A. Then, the products of Step A, B and Care used in each subsequent step (i.e., Steps B, C and D) so that(-)-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1-H-pyrrole-2,5-dioneand its 1-methylpiperazine salt are obtained in Step D.

EXAMPLE 30(+)-3-[2-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out substantially as described in Example 15,Steps A and B except that(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyricacid is substitued for the corresponding racemic compound used inExample 15, Step A. There is obtained in Step A,(+)-4-[((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramidewhich is then used in Step B in place of the corresponding racemiccompound to obtain(+)3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 31(-)3-[2((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-Methylpiperazine Salt

The preparation is carried out substantially as described in Example 15,Steps A and B except that(-)-4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyricacid is substituted for the corresponding racemic compound used inExample 15, Step A. There is obtained in Step A,(-)-4[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramidewhich is then used in Step B in place of the corresponding racemiccompound to obtain(-)3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneand its 1-methylpiperazine salt.

EXAMPLE 32 (+)-Enantiomers of the two diastereomers of3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dioneStep A: (+)-Enantiomers of the two diastereomers of(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide

To a stirred solution of(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide(3.4 g, 0.01 mole) in ethanol (50 ml) is added sodium borohydride (380mg, 0.01 mole). After one hour, another portion of sodium borohydride(380 mg, 0.01 mole) is added. The reaction is stirred for 3 hours,poured into ice water, extracted with ethyl acetate, washed with waterand dried over magnesium sulfate. Evaporation of the ethyl acetate givesa mixture of the (+)-enantiomers of the two diastereomers of(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide.

Step B: (+)-Enantiomers of the two diastereomers of3-(6,7-dichloro-2-cyclopentyl)-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

In an atmosphere of dry nitrogen, a mixture of the (+)-enantiomers ofthe two diastereomers of(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)acetamide(3.4 g, 0.01 mole) and diethyl oxalate (1.57 g, 0.0107 mole) aredissolved in dimethylformamide (20 ml) and stirred in an ice bath.Potassium tert. butoxide (2.6 g, 0.023 mole) is added in 2 portions at a10 minute interval. The reaction mixture is stirred at 25° for 18 hours,poured into water, acidifed with hydrochloric acid, extracted intoether, washed with water and dried over magnesium sulfate. Evaporationof the ether at reduced pressure gives a mixture of the two(+)-enantiomers of the two diastereomers of3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione.Each of these two diastereomers consists of one enantiomer which areseparated by chromatography to give the two pure diastereomrs designatedas the (+)-α-diastereomer and (+)-β-diastereomer.

EXAMPLE 33 (+)-Enantiomers of the two diastereomers of(+)-3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dioneStep A: (+)-Enantiomers of the two diastereomers of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramide

The preparation is carried out essentially as described in Example 15,Step A except that(+)-4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyricacid is substituted for the corresponding racemate used in Example 15,Step A. There is thus obtained (+)-enantiomers of the two diastereomerof4-[(6,7-dichloro-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butyramide.

Step B: (+)-Enantiomers of the two diastereomers of4-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-1-methyl-1H-inden-5-yl)oxy]butyramide

The synthesis is conducted substantially as described in Example 19,Step A except that an equimolar amount of a mixture of the two(+)-enantiomers of the two diastereomers of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-butyramideis substituted for the(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-acetamidethat is used in Example 19, Step A. There is thus obtained(+)-enantiomers of the two diastereomers of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-1-methyl-1H-inden-5-yl)oxy]butyramide.

Step C: (+)-Enantiomers of the two diastereomers of3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)-oxy)ethyl]4-hydroxy-1H-pyrrole-2,5-dione

The preparation is conducted substantially as described in Example 1,Step D except that an equimolar amount of the two (+)-enantiomers of thetwo diastereomers of4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]butylamideis substituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideused in Example 1, Step D. There is thus obtained a mixture of the(+)-enantiomers of the two diastereomers of3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy)-ethyl]-4-hydroxy-1H-pyrrole-2,5-dione.Each diastereomer consists of one pure enantiomer which are separated bychromatography to give the two pure diastereomers designated as(+)-α-diastereomer and (+)-β-diastereomer since they were derived fromthe (+)-enantiomer described in Step A.

EXAMPLE 34 (+)-Enantiomers of the diastereomers of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dioneStep A: (+)-Enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamide

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Step C except that an equimolar amount of(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]aceticacid is substituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)aceticacid used in Example 1, Step C. There is thus obtained first the(+)-enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]-acetylchloride and then (+)-enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamide.

Step B: (+)-Enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]acetamide

The preparation is carried out by following substantially the proceduresdescribed in Example 19, Step A, except that an equimolar amount of(+)-enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetamideis substituted for the(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideused in Example 19, Step A. There is thus obtained (+)-enantiomers ofthe (+)-diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]acetamide.

Step C: (+)-Enantiomers of the diastereomers of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dione

The preparation is carried out by following substantially the proceduresdescribed in Example 1, Step D, except that an equimolar amount of(+)-enantiomers of the diastereomers of[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]acetamideis substituted for the(+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamideused in Example 1, Step D. There is thus obtained a mixture of the(+)-enantiomers of the diastereomers of3-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-hydroxy-2-methyl-1H-inden-5-yl)oxy]-4-hydroxy-1H-pyrrole-2,5-dionewhich consists of two diastereomers each of which are composed of a pureenantiomer. These diastereomers are separated by chromatography to givethe pure diastereomers which are designated as (+)-α-diastereomer andthe (+)-β-diastereomer since they are derived from the (+)-enantiomerdescribed in Step A.

EXAMPLE 35 Parenteral Solution of the 1-Methylpiperazine Salt of(+)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

(+)-3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione1-methylpiperazine salt (Example 1, Step D) (125.4 mg) is dissolved bystirring and warming with a sufficient volume of pyrogen-free water togive a final volume of 20 ml. The solution is then sterilized byfiltration, the concentration of the active agent in the final solutionis 0.5%.

EXAMPLE 36 Parenteral Solution of the Sodium Salt of(+)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

(+)-3-(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 1, Step D) (500 mg) is dissolved by stirring and warming with0.25N sodium bicarbonate (5.4 ml). The solution is diluted to 10 ml andsterilized by filtration. All the water that is used in the preparationis pyrogen-free. The concentration of the active agent in the finalsolution is 5%.

EXAMPLE 37 Parenteral Solution of the Sodium Salt of(+)-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

(+)-(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 26, Step D) (500 mg) is dissolved by stirring and warming with0.25N sodium bicarbonate (5 ml). The solution is diluted to 10 ml andsterilized by filtration. All the water that is used in the preparationis pyrogen-free. The concentration of the active agent in the finalsolution is 5%.

EXAMPLE 38 Parenteral Solution of Sodium Salt of(+)-3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione

(+)-3-[2-((6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione(Example 30, Step B) (500 mg) is dissolved by stirring and warming with0.05N sodium bicarbonate solution (4.9 ml). The solution is diluted to10 ml and sterilized by filtration. All the water that is used in thepreparation is pyrogen-free. The concentration of the active agent inthe final solution is 5%.

EXAMPLE 39 Parenteral Solution of the Sodium Salt of(-)-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione

(-)-(6,7-Dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 29, Step D) (500 mg) is dissolved by stirring and warming with0.25N sodium bicarbonate solution (5.4 ml). The solution is diluted to10 ml and sterilized by filtration. All the water that is used in thepreparation is pyrogen-free. The concentration of the active agent inthe final solution is 5%.

Similar parenteral solutions can be prepared by replacing the activeingredient of the above example by any of the other4-hydroxy-1H-pyrrole-2,5-dione compounds of this invention.

EXAMPLE 40 Dry-Filled Capsules Containing 100 mg of Active IngredientPer Capsule

    ______________________________________                                                           Per Capsule                                                ______________________________________                                        (+)-3-(6,7-Dichloro-2-cyclo-                                                                       100 mg                                                   pentyl-2,3-dihydro-2-methyl-                                                  1-oxo-1H--inden-5-yl)-4-hydroxy-                                              1H--pyrrole-2,5-dione                                                         Lactose               99 mg                                                   Magnesium Stearate    1 mg                                                    Capsule (Size No. 1) 200 mg                                                   ______________________________________                                    

The(+)-3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 1, Step D) is reduced to a No. 60 powder and then the lactoseand magnesium stearate are passed through a No. 60 bolting cloth ontothe powder and the combined ingredients admixed for 10 minutes and thenfilled into a No. 1 dry gelatin capsule.

EXAMPLE 41 Dry-Filled Capsules Containing 100 mg of Active IngredientPer Capsule

    ______________________________________                                                           Per Capsule                                                ______________________________________                                        (+)-(2-Butyl-6,7-dichloro-2-                                                                       100 mg                                                   cyclopentyl-2,3-dihydro-1-oxo-                                                1H--inden-5-yl)-4-hydroxy-1H--                                                pyrrole-2,5-dione                                                             Lactose               99 mg                                                   Magnesium Stearate    1 mg                                                    Capsule (Size No. 1) 200 mg                                                   ______________________________________                                    

The(+)-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 26, Step D) is reduced to a No. 60 powder and then the lactoseand magnesium stearate are passed through a No. 60 bolting cloth ontothe powder and the combined ingredients admixed for 10 minutes and thenfilled into a No. 1 dry gelatin capsule.

EXAMPLE 42 Dry-Filled Capsules Containing 100 mg of Active IngredientPer Capsule

    ______________________________________                                                          Per Capsule                                                 ______________________________________                                        (+)-3-[2-((6,7-dichloro-2-cyclo-                                                                  100 mg                                                    pentyl-2,3-dihydro-2-methyl-1-                                                oxo-1H--inden-5-yl)oxy)ethyl]-4-                                              hydroxy-1H--pyrrole-2,5-dione                                                 Lactose              99 mg                                                    Magnesium Stearate   1 mg                                                     Capsule (Size No. 1)                                                                              200 mg                                                    ______________________________________                                    

The(+)-3-[2-((6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)ethyl]-4-hydroxy-1H-pyrrole-2,5-dione(Example 30, Step B) is reduced to a No. 60 powder and then the lactoseand magnesium stearate are passed through a No. 60 bolting cloth ontothe powder and the combined ingredients admixed for 10 minutes and thenfilled into a No. 1 dry gelatin capsule.

EXAMPLE 43 Dry-Filled Capsules Containing 100 mg of Active IngredientPer Capsule

    ______________________________________                                                          Per Capsule                                                 ______________________________________                                        (-)-(6,7-Dichloro-2,3-dihydro-                                                                    100 mg                                                    2-methyl-1-oxo-2-phenyl-1H--                                                  inden-5-yl)-4-hydroxy-1H--                                                    pyrrole-2,5-dione                                                             Lactose              99 mg                                                    Magnesium Stearate   1 mg                                                     Capsule (Size No. 1)                                                                              200 mg                                                    ______________________________________                                    

The(-)-(6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione(Example 29, Step D) is reduced to a No. 60 powder and then the lactoseand magnesium stearate are passed through a No. 60 bolting cloth ontothe powder and the combined ingredients admixed for 10 minutes and thenfilled into a No. 1 dry gelatin capsule.

Similar dry-filled capsules can be prepared by using any of the othercompounds of this invention.

What is claimed is:
 1. A method of treating persons with grey matteredema which comprises administering to such a person an effective amountof a compound of the formula: ##STR19## in which R and R' are differententities and wherein: R is C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkyl-loweralkyl, aryl selected from phenyl, halophenyl, methoxyphenyl,hydroxyphenyl, thienyl, aralkyl selected from benzyl and phenethyl,lower alkyl, lower alkenyl, lower alkynyl wherein the term lowerindicates up to four carbon atoms;R' is lower alkyl, lower alkenyl,lower alkynyl; X and Y are each selected from methyl and chloro.